EpoR stimulates rapid cycling and larger red cells during mouse and human erythropoiesis

Hidalgo, Daniel; Bejder, Jacob; Pop, Ramona; Gellatly, Kyle; Scalf, S. Maxwell; Eastman, Anna E.; Chen, Jane-Jane; Zhu, Lihua Julie; Heuberger, Jules; Guo, Shangqin; Koury, Mark J.; Nordsborg, Nikolai Baastrup; Socolovsky, Merav

doi:10.1038/s41467-021-27562-4

Cited by 34 publications

(26 citation statements)

References 112 publications

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“…The results correspond to the proposed mechanism that glucocorticoids increase the erythroid progenitor colonyforming unit erythroid formation by stimulating the self-renewal of the burst-forming unit erythroid (13,29). In addition, we did not observe an increased mean cell volume or red cell distribution width as expected when erythropoiesis is increased via high erythropoietin receptor signaling (30). Of interest, the activation of hypoxia-induced factor 1α synergized with glucocorticoid treatment in vitro enhances the colony-forming unit erythroid formation sevenfold compared to glucocorticoids alone (13).…”

Section: Discussionsupporting

confidence: 90%

Glucocorticoids Accelerate Erythropoiesis in Healthy Humans—Should the Use in Sports Be Reevaluated?

Nordsborg¹,

Bonne²,

Andersen

et al. 2023

Medicine &Amp; Science in Sports &Amp; Exercise

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PurposeThe World Anti-Doping Agency prohibits glucocorticoid administration in competition but not in periods out of competition. Glucocorticoid usage is controversial as it may improve performance, albeit debated. A hitherto undescribed but performance-relevant effect of glucocorticoids in healthy humans is accelerated erythropoiesis. We investigated whether a glucocorticoid injection accelerates erythropoiesis, increases total hemoglobin mass, and improves exercise performance.MethodsIn a counterbalanced, randomized, double-blinded, placebo-controlled crossover design (3 months washout), 10 well-trained males (peak oxygen uptake, 60 ± 3 mL O2·min−1·kg−1) were injected with 40 mg triamcinolone acetonide (glucocorticoid group) or saline (placebo group) in the gluteal muscles. Venous blood samples collected before and 7–10 h, 1, 3, 7, 14, and 21 d after treatment were analyzed for hemoglobin concentration and reticulocyte percentage. Hemoglobin mass and mean power output in a 450-kcal time trial were measured before as well as 1 and 3 wk after treatment.ResultsA higher reticulocyte percentage was evident 3 d (19% ± 30%, P < 0.05) and 7 d (48% ± 38%, P < 0.001) after glucocorticoid administration, compared with placebo, whereas hemoglobin concentration was similar between groups. Additionally, hemoglobin mass was higher (P < 0.05) 7 d (glucocorticoid, 886 ± 104 g; placebo, 872 ± 103 g) and 21 d (glucocorticoid, 879 ± 111 g; placebo, 866 ± 103 g) after glucocorticoid administration compared with placebo. Mean power output was similar between groups 7 d (glucocorticoid, 278 ± 64 W; placebo, 275 ± 62 W) and 21 d (glucocorticoid, 274 ± 62 W; placebo, 275 ± 60 W) after treatment.ConclusionsIntramuscular injection of 40 mg triamcinolone acetonide accelerates erythropoiesis and increases hemoglobin mass but does not improve aerobic exercise performance in the present study. The results are important for sport physicians administering glucocorticoids and prompt a reconsideration of glucocorticoid usage in sport.

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Section: Discussionsupporting

confidence: 90%

Glucocorticoids Accelerate Erythropoiesis in Healthy Humans—Should the Use in Sports Be Reevaluated?

Nordsborg¹,

Bonne²,

Andersen

et al. 2023

Medicine &Amp; Science in Sports &Amp; Exercise

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“…EPO is a hormone produced by the kidneys and secreted in situations of hypoxia; its principal function is to induce hematopoiesis ( 25 , 26 ). The increase in hematopoiesis which happens through erythropoietin results in an increase of the size of the circulating RBCs and consequently in an increase of the rate of RDW (anisocytosis) ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

The effect of SGLT-2i administration on red blood cell distribution width in patients with heart failure and type 2 diabetes mellitus: A randomized study

Κατσιάδας

Xanthopoulos

Giamouzis

et al. 2022

Front. Cardiovasc. Med.

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BackgroundRecent studies suggest that the pivotal mechanism of sodium glucose co-transporter-2 inhibitors (SGLT-2i) favorable action in patients with heart failure (HF) and type 2 diabetes mellitus (DM) is the stimulation of erythropoiesis via an early increase in erythropoietin (EPO) production which leads to hematocrit rise. Red blood cell distribution width (RDW) is a simple hematological parameter which reflects the heterogeneity of the red blood cell size (anisocytosis). Since, EPO has been also implicated in the pathophysiology of RDW increase, the current mechanistic study examined the effect of SGLT-2i administration on red blood cells size (RDW) in patients with HF and DM.MethodsThe present was a prospective single-center study. Patients (N=110) were randomly assigned to dapagliflozin (10 mg a day on top of antidiabetic treatment) or the control group. Inclusion criteria were: (a) age > 18 years, (b) history of type 2 DM and hospitalization for HF exacerbation within 6 months. The evaluation of patients (at baseline, 6 and 12 months) included clinical assessment, laboratory blood tests, and echocardiography. Data were modeled using mixed linear models with dependent variable the RDW index. In order to find factors independently associated with prognosis (1-year death or HF rehospitalization), multiple logistic regression was conducted with death or HF rehospitalization as dependent variable.ResultsAn RDW increase both after 6 and after 12 months was observed in the SGLT-2i (dapagliflozin) group (p < 0.001 for all time comparisons), whereas RDW didn't change significantly in the control group. The increase in RDW was positively correlated with EPO, while negatively correlated with ferritin and folic acid (p < 0.005 for all). Baseline RDW was significantly associated with 1-year death or rehospitalization, after adjusting for group (SGLT-2i vs. control), age, gender, smoking and BMI at baseline.ConclusionRDW increased with time in patients with HF and DM who received SGLT-2i (dapagliflozin). The increased RDW rates in these patients may stem from the induction of hemopoiesis from dapagliflozin. Baseline RDW was found to be independently associated with outcome in patients with HF and DM.

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“…Recent studies have established a link between cell cycle duration and regulation of red cell volume during terminal erythroid differentiation in the mouse. 23 We propose the use of combined immunophenotyping with cell cycle analyses in isolated bone marrow from patients with DBA could provide new insights into volume regulation.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and proteomic characterization of the human erythroid progenitor continuum reveal dynamic changes in cell cycle and in metabolic pathways

Papoin,

Yan,

Leduc

et al. 2023

American J Hematol

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Human erythropoiesis is a complex process leading to the production of 2.5 million red blood cells per second. Following commitment of hematopoietic stem cells to the erythroid lineage, this process can be divided into three distinct stages: erythroid progenitor differentiation, terminal erythropoiesis, and reticulocyte maturation. We recently resolved the heterogeneity of erythroid progenitors into four different subpopulations termed EP1–EP4. Here, we characterized the growth factor(s) responsiveness of these four progenitor populations in terms of proliferation and differentiation. Using mass spectrometry‐based proteomics on sorted erythroid progenitors, we quantified the absolute expression of ~5500 proteins from EP1 to EP4. Further functional analyses highlighted dynamic changes in cell cycle in these populations with an acceleration of the cell cycle during erythroid progenitor differentiation. The finding that E2F4 expression was increased from EP1 to EP4 is consistent with the noted changes in cell cycle. Finally, our proteomic data suggest that the protein machinery necessary for both oxidative phosphorylation and glycolysis is present in these progenitor cells. Together, our data provide comprehensive insights into growth factor‐dependence of erythroid progenitor proliferation and the proteome of four distinct populations of human erythroid progenitors which will be a useful framework for the study of erythroid disorders.

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EpoR stimulates rapid cycling and larger red cells during mouse and human erythropoiesis

Cited by 34 publications

References 112 publications

Glucocorticoids Accelerate Erythropoiesis in Healthy Humans—Should the Use in Sports Be Reevaluated?

Glucocorticoids Accelerate Erythropoiesis in Healthy Humans—Should the Use in Sports Be Reevaluated?

The effect of SGLT-2i administration on red blood cell distribution width in patients with heart failure and type 2 diabetes mellitus: A randomized study

Phenotypic and proteomic characterization of the human erythroid progenitor continuum reveal dynamic changes in cell cycle and in metabolic pathways

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